How intrinsically disordered regions shape the function of CREB-binding protein.

Abstract

CREB-binding protein (CBP) is a histone acetyltransferase and transcriptional co-activator that operates across the genome at cis-regulatory elements (CREs) to regulate gene expression. Comprising the majority of the protein, CBP has intrinsically disordered regions (IDRs) that separate its folded domains. Whilst previously regarded as passive linkers, active roles for these IDRs within CBP are beginning to be uncovered. Firstly, the flexibility afforded by these regions and the presence of binding motifs within them establish CBP as an interaction specialist that is able to interact with many binding partners at diverse CREs. In addition, the IDRs of CBP allow it to undergo liquid-liquid phase separation, forming condensates with emerging roles in transcription. Finally, an IDR within CBP performs an autoregulatory function that makes histone acetyltransferase activity sensitive to changing conditions within the cell. To build a comprehensive understanding of CBP function going forwards, it will be necessary to consider the contributions of the IDRs in addition to the structured domains of CBP and how these are integrated for the regulation of this key transcriptional protein.